Copper-catalyzed regioselective ortho C-H cyanation of vinylarenes

Article abstract of DOI:10.1002/anie.201402449

A copper-based catalytic technique for the regioselective ortho C-H cyanation of vinylarenes has been developed. This method provides an effective means for the selective functionalization of vinylarene derivatives. A copper-catalyzed cyanative dearomatiz

Full text of DOI:10.1002/anie.201402449

Angewandte
Chemie
DOI: 10.1002/anie.201402449
À
C H Activation
À
Copper-Catalyzed Regioselective ortho C H Cyanation of
Vinylarenes**
Yang Yang and Stephen L. Buchwald*
Dedicated to the MPI fꢀr Kohlenforschung on the occasion of its centenary
À
Abstract: A copper-based catalytic technique for the regiose-
a directing group for the C H functionalization event
(Scheme 1). Overall, this method introduces a synthetically
À
lective ortho C H cyanation of vinylarenes has been devel-
oped. This method provides an effective means for the selective
functionalization of vinylarene derivatives. A copper-catalyzed
cyanative dearomatization mechanism is proposed to account
for the regiochemical course of this reaction.
versatile cyano group,[5] while simultaneously performing
a catalytic anti-Markovnikov hydrofunctionalization of the
olefin.[6]
As a part of our work to develop catalytic methods for the
enantioselective difunctionalization of olefins,[7,8] we sought
À
T
ransition-metal-catalyzed direct C H functionalization is
an attractive strategy to streamline chemical synthesis.[1,2]
Table 1: Optimization of reaction conditions.[a]
À
During the past decade, chelation-assisted C H activation
has been employed to devise a range of synthetically useful
functionalization reactions of aromatic compounds.[1] In these
processes, relatively strong s-directing groups, such as pyr-
idines[1b,c,h] and carbonyls,[1a,e,f,g] are usually required to coor-
dinate to the transition-metal center, thereby enhancing
reactivity as well as controlling site selectivity. In contrast,
=
weakly coordinating p-directing groups, such as C C bonds,
have rarely been utilized, and in particular, the ortho-selective
[3,4]
À
C H functionalization of styrenes remains a challenge.
Entry
L
Yield [%]
Herein we report a combined copper-catalyzed boryla-
3a
3b
À
tion/ortho C H cyanation reaction of vinylarenes. In this
1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
–
84
90
55
70
25
59
63
0
<5
0
10
6
7
11
9
0
0
<5
0
0
=
process, the C C bond is used as both a reaction site and
2[b]
3
4
5
6
7
8
9
95
88
0
10[c]
11[d]
12[e]
À
Scheme 1. Copper-catalyzed borylation/ortho C H cyanation of styr-
enes. Pin=pinacol.
0
[a] Reaction conditions: 1 (0.20 mmol), 2 (0.30 mmol), CuCl
(0.040 mmol), L (0.044 mmol), LiOtBu (0.31 mmol), THF (0.50 mL),
608C, 12 h. Yields of 3a–d were determined by 1H NMR analysis of the
crude reaction mixture using 1,1,2,2-tetrachloroethane as an internal
standard. [b] 1,4-Dioxane (0.70 mL), 808C, 12 h. [c] CuCl (5 mol%), L8
(6 mol%), 1.0 mmol scale. [d] TsCN was used instead of 2. [e] In the
absence of CuCl and ligand. THF=tetrahydrofuran, Ts=4-toluenesul-
fonyl.
[*] Y. Yang, Prof. Dr. S. L. Buchwald
Department of Chemistry, Massachusetts Institute of Technology
77 Massachusetts Avenue, Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
[**] We thank the National Institutes of Health (GM46059) for financial
support. We are grateful to Dr. Aaron C. Sather (MIT), Dr. Yi-Ming
Wang (MIT), and Dr. Daniel T. Cohen (MIT) for insightful dis-
cussions and help with the preparation of this manuscript. MIT has
patents on some of the ligands used in this study from which S.L.B.
as well as current or former co-workers receive royalty payments.
The content is solely the responsibility of the authors and does not
necessarily represent the official views of the National Institute of
Health.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402449.
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5% yield as indicated by 1H NMR spectroscopy. Further
experimentation revealed that replacement of the phosphine-
bound cyclohexyl groups with phenyl (L2) or tert-butyl (L3)
resulted in catalysts which were less effective. Increasing the
steric bulk of the ligandꢀs biaryl backbone did not lead to
further improvement (entries 5 and 6). Employing bidentate
phosphine ligands such as dppp (L6) also furnished the C1-
cyanation product, albeit in lower yields, while the use of
binap (L7) provided less than 5% product under otherwise
identical reaction conditions. Among various bidentate phos-
phine ligands examined, DPPBz (L8) gave the best results,
thus providing 3a in 95% yield along with less than 5% of
3c.[12] Other commonly used electrophilic cyanating agents
such as TsCN were ineffective for the current transformation
(entry 11).
We next explored the substrate scope with respect to the
vinylarene component (Scheme 2). A variety of 2-vinylnaph-
thalenes bearing electron-donating or electron-withdrawing
functional groups were converted into the C1-cyanated
product in good yields (4b–h). C3 cyanation was not observed
for any of the cases examined. Sterically hindered substrates
could be successfully transformed with this method (4i and
4j), and 1-vinylnaphthalenes also represented excellent sub-
strates (4k and 4l). Further, a heterocyclic vinylarene (4m) as
well as those bearing pendent heterocyclic motifs (4n–p) were
compatible. By using the L8-based catalyst, 2-(prop-1-en-2-
yl)naphthalene and 2-(prop-1-en-1-yl)naphthalene also
reacted to provide the cyanation products, albeit in lower
yields (see the Supporting Information). Finally, styrene can
also be cyanated in a similar fashion (73%) using the L8-
based catalyst, although other simple aromatic substrates
such as 4-methoxystyrene afforded lower yields of the desired
product (30–40%).
To demonstrate the synthetic versatility of the products
derived from this method, several derivatization reactions
were performed (Scheme 3). Oxidation of the boronate
afforded the alcohol 5a,[13] while the BCl3-mediated amina-
Scheme 2. Substrate scope of vinylarenes. Reaction conditions: vinyl-
arene (0.20–1.0 mmol), 2 (1.2 equiv), B2Pin2 (1.1–1.2 equiv), LiOtBu
(1.5 equiv), CuCl (20 mol%), L1 (22 mol%), 1,4-dioxane (0.30m),
808C or L8 (22 mol%), THF (0.40m), 608C, 12 h. Yields reported are
that of the isolated material. Yields within parentheses were deter-
mined by 1H NMR analysis of the crude reaction mixture using 1,1,2,2-
tetrachloroethane as an internal standard. Yield of isolated product
were lower than yields determined by 1H NMR spectroscopy because
of product decomposition on silica gel. Boc=tert-butoxycarbonyl,
MOM=methoxymethyl, TMS=trimethylsilyl.
to use the benzylcopper intermediate B, generated from
hydrocupration[7] or borocupration[9] of the styrenes A, in
a subsequent electrophilic functionalization process. In an
attempt to develop a cyanoborylation reaction, we unexpect-
À
edly found that the ortho C H functionalized product 3a was
generated in 90% yield upon treatment of 2-vinylnaphtha-
lene (1) with the electrophilic cyanating agent NCTS (2)[10] in
the presence of a copper catalyst derived from CyJohnPhos[11]
(L1; Table 1, entries 1 and 2). Notably, cyanation at the less
sterically congested C3-position (3b) was not observed and
the benzylic cyanation product 3c was obtained in less than
Scheme 3. Derivatization of borylation/cyanation products. Reaction
conditions: a) NaOH/H2O2, RT, 2 h, 85%. b) BCl3, CH2Cl2, RT, 4 h,
then BnN3, 08C, 16 h, 63%. c) ArCl, 5 mol% RuPhos Precat, 5 mol%
RuPhos, K3PO4, toluene/H2O, 808C, 12 h, 60%. d) Conc. HCl/MeOH,
608C, 12 h, 95%. e) NiCl2·6H2O, NaBH4, Boc2O, MeOH, 08C to RT,
1 h, 65%. f) NaN3, ZnBr2, H2O/iPrOH, 1008C, 48 h, 92%.
2
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tion with benzyl azide provided the amine 5b.[14] Suzuki–
Miyaura coupling using our RuPhos-based palladacycle
precatalyst[15] delivered the unsymmetrical 1,2-diarylethane
bearing a heterocyclic core (5c). Furthermore, 5a was
converted into the lactone 5d, amide 5e,[16] and tetrazole
5 f[17] in excellent yields.
A great deal of effort has been devoted to the selective
functionalization of the biaryl backbone of binol in an
attempt to access new catalysts for enantioselective trans-
À
formations. However, the regioselective C H functionaliza-
tion of binol derivatives at the C4- or C5-position remains
underdeveloped (Scheme 4).[18] To further demonstrate the
Scheme 4. Regioselective cyanation of binol scaffolds.
utility of our method, we converted 6a and 6b into the
corresponding cyanated products 7a and 7b, respectively. In
Scheme 6. Mechanistic studies.
À
both examples, a single C H cyanated isomer was generated.
Additionally, the fully substituted and differentiated benzene
ring of 7b is generated with acceptable yield.[19]
rates, we found that converting 11 into 4h in the presence of 9
did not result in deuterium incorporation, whereas the
amount of deuterium incorporated in 10 was unaffected.
Furthermore, a competition experiment between 9 and
1 showed a kinetic isotope effect (KIE) of 0.98 Æ 0.02, which
is suggestive that the rate-determining step precedes hydro-
gen migration.
À
We were also able to effect the formal ortho C H
cyanation of 2-vinylnaphthalenes by treating 5a with DBU
in the presence of MsCl at room temperature to furnish 8 in
85% yield (Scheme 5). By regenerating the olefin, the C1
Based on these results, we propose that the current
reaction proceeds through a cyanative dearomatization
mechanism (Scheme 7). Transmetalation of the phosphine-
ligated copper catalyst 12 with the diboron reagent provides
13, which undergoes subsequent borocupration to afford the
À
Scheme 5. Unmasking the boronic ester: Formal ortho C H cyanation
of vinylarenes. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, Ms=metha-
nesulfonyl.
selectivity that we observe complements that of other
À
directed C H activation processes, where the functionaliza-
tion of less sterically hindered C3 is usually favored.[20]
To gain insight into the reaction mechanism of this
process, we prepared 1-deutero-2-vinylnaphthalene (9) and
subjected it to the standard reaction conditions (Scheme 6). It
was found that 88% of the deuterium of 9 was incorporated
into 10 at the benzylic position, thus indicating that a formal
1,3-hydrogen transposition has taken place. In addition, we
were able to demonstrate that this hydrogen migration is
likely an intramolecular process with respect to the vinyl-
naphthalene substrate by performing a crossover experiment
using 9 and 11. After confirming that 9 and 11 react at similar
Scheme 7. Mechanistic proposal.
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benzylcopper 14a.[9a,h] Electrophilic cyanation of 14a with
NCTS (2) proceeds in an SE2’ fashion, thus delivering the
dearomatized intermediate 16, which then undergoes a rapid
hydrogen transfer to generate the C1-cyanated product.[21–24]
Cyanation at C3 (17) would disrupt the aromaticity of both
benzene rings and is therefore disfavored. At this point the
exact reason for the favorable C1 cyanation over benzylic
cyanation remains unclear. We are performing computational
studies to gain an accurate understanding into this regio-
chemical outcome.
[8] R. Zhu, S. L. Buchwald, Angew. Chem. 2013, 125, 12887; Angew.
Chem. Int. Ed. 2013, 52, 12655.
[9] Examples of borocupration of styrenes: a) D. S. Laitar, E. Y.
Tsui, J. P. Sadighi, Organometallics 2006, 25, 2405; b) V. Lillo,
M. R. Fructos, J. Ramꢁrez, A. A. C. Braga, F. Maseras, M. M.
Dꢁaz-Requejo, P. J. Pꢂrez, E. Fernꢃndez, Chem. Eur. J. 2007, 13,
2614; c) Y. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2009, 131,
3160; d) C. Zhong, S. Kunii, Y. Kosaka, M. Sawamura, H. Ito, J.
Am. Chem. Soc. 2010, 132, 11440; e) H. Ito, T. Toyoda, M.
Sawamura, J. Am. Chem. Soc. 2010, 132, 5990; f) R. Corberꢃn,
N. W. Mszar, A. H. Hoveyda, Angew. Chem. 2011, 123, 7217;
Angew. Chem. Int. Ed. 2011, 50, 7079; g) N. Matsuda, K. Hirano,
T. Satoh, M. Miura, J. Am. Chem. Soc. 2013, 135, 11440;
Computational studies: h) L. Dang, H. Zhao, Z. Lin, T. B.
Marder, Organometallics 2007, 26, 2824.
In conclusion, we have developed a copper-catalyzed
À
ortho C H cyanation of vinylarenes. This protocol provides
an effective means to access an array of synthetically versatile
building blocks which can be easily transformed into a variety
[10] NCTS (2) is a safe and bench-stable crystalline compound which
can be easily prepared from tosyl chloride and phenylurea. For
the synthesis of NCTS: a) F. Kurzer, J. Chem. Soc. 1949, 1034;
b) F. Kurzer, J. Chem. Soc. 1949, 3029; For the application of
NCTS in electrophilic cyanation: c) P. Anbarasan, H. Neumann,
M. Beller, Angew. Chem. 2011, 123, 539; d) Angew. Chem. Int.
Ed. 2011, 50, 519; e) P. Anbarasan, H. Neumann, M. Beller,
Chem. Eur. J. 2011, 17, 4271; f) Y. Yang, Y. Zhang, J. Wang, Org.
Lett. 2011, 13, 5068; g) T.-J. Gong, B. Xiao, W.-M. Cheng, W. Su,
J. Xu, Z.-J. Liu, L. Liu, Y. Fu, J. Am. Chem. Soc. 2013, 135, 10630;
h) M. Chaitanya, D. Yadagiri, P. Anbarasan, Org. Lett. 2013, 15,
4960; i) W. Liu, L. Ackermann, Chem. Commun. 2014, 50, 1878.
[11] J. P. Wolfe, S. L. Buchwald, Angew. Chem. 1999, 111, 2570;
Angew. Chem. Int. Ed. 1999, 38, 2413.
[12] For a detailed ligand evaluation, see the Supporting Information.
[13] The structure of 5a was confirmed by X-ray diffraction analysis.
CCDC 986749 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
À
of complex molecules. This C H functionalization process
features unique site selectivity, which originates from
a copper-catalyzed electrophilic cyanative dearomatization
mechanism. Designing new catalysts to broaden the substrate
scope, developing enantioselective variants of the current
transformation, and engaging other electrophiles of signifi-
cant synthetic utility in this process are topics of ongoing
investigations in our laboratory.
Received: February 14, 2014
Published online: && &&, &&&&
À
Keywords: C H activation · copper · dearomatization ·
ligand design · synthetic methods
.
À
[1] Selected reviews on directed C H activation: a) F. Kakiuchi, S.
Sekine, Y. Tanaka, A. Kamatani, M. Sonoda, N. Chatani, S.
Murai, Bull. Chem. Soc. Jpn. 1995, 68, 62; b) C.-H. Jun, J.-B.
Hong, D.-Y. Lee, Synlett 1999, 1; c) O. Daugulis, H.-Q. Do, D.
Shabashov, Acc. Chem. Res. 2009, 42, 1074; d) M. Albrecht,
Chem. Rev. 2010, 110, 576; e) D. A. Colby, R. G. Bergman, J. A.
Ellman, Chem. Rev. 2010, 110, 624; f) C. S. Yeung, V. M. Dong,
Chem. Rev. 2011, 111, 1215; g) K. M. Engle, T.-S. Mei, M. Wasa,
J.-Q. Yu, Acc. Chem. Res. 2012, 45, 788; h) S. R. Neufeldt, M. S.
Sanford, Acc. Chem. Res. 2012, 45, 936.
À
[2] Selected reviews on other C H functionalizations: a) I. A.
[14] K. Kubota, E. Yamamoto, H. Ito, J. Am. Chem. Soc. 2013, 135,
2635.
[15] N. C. Bruno, M. T. Tudge, S. L. Buchwald, Chem. Sci. 2013, 4,
916.
[16] S. Caddick, A. K. K. Haynes, D. B. Judd, M. R. V. Williams,
Tetrahedron Lett. 2000, 41, 3513.
[17] Z. P. Demko, K. B. Sharpless, J. Org. Chem. 2001, 66, 7945.
[18] a) J. M. Brunel, Chem. Rev. 2005, 105, 857; b) Y. Chen, S. Yekata,
A. K. Yudin, Chem. Rev. 2003, 103, 3155; c) M. Berthod, G.
Mignani, G. Woodward, M. Lemaire, Chem. Rev. 2005, 105, 1801.
[19] For reviews on alternative methods to prepare fully substituted
arenes, see: a) P. R. Chopade, J. Louie, Adv. Synth. Catal. 2006,
348, 2307; b) W. A. L. van Otterlo, C. B. de Koning, Chem. Rev.
2009, 109, 3743.
[20] For an example, see: D. Kalyani, A. R. Dick, W. Q. Anani, M. S.
Sanford, Tetrahedron 2006, 62, 11483.
[21] For a recent review on the chemistry of benzylmetal species, see:
B. M. Trost, L. C. Czabaniuk, Angew. Chem. 2014, 126, 2868;
Angew. Chem. Int. Ed. 2014, 53, 2826.
Mkhalid, J. H. Barnard, T. B. Marder, J. M. Murphy, J. F.
Hartwig, Chem. Rev. 2010, 110, 890; b) A. E. Wendlandt,
A. M. Suess, S. S. Stahl, Angew. Chem. 2011, 123, 11256;
Angew. Chem. Int. Ed. 2011, 50, 11062; c) H. M. L. Davies, D.
Morton, Chem. Soc. Rev. 2011, 40, 1857.
À
[3] For a palladium-catalyzed C H activation directed by an ortho
=
allylic C C bond, see: P. Gandeepan, C.-H. Cheng, J. Am. Chem.
Soc. 2012, 134, 5738. Styrenes were unreactive under these
reaction conditions.
[4] M. Tobisu, I. Hyodo, M. Onoe, N. Chatani, Chem. Commun.
2008, 6013.
[5] R. C. Larock, Comprehensive Organic Transformations, Wiley-
VCH, New York, 1988.
[6] For a review, see: M. Beller, J. Seavad, A. Tillack, H. Jiao,
Angew. Chem. 2004, 116, 3448; Angew. Chem. Int. Ed. 2004, 43,
3368; For a recent example: G. Dong, P. Teo, Z. K. Wickens,
R. H. Grubbs, Science 2011, 333, 1609.
[7] For example, we have recently demonstrated the utility of
benzylcopper intermediates generated from hydrocupration of
styrenes in an enantioselective amination process: S. Zhu, N.
Niljianskul, S. L. Buchwald, J. Am. Chem. Soc. 2013, 135, 15746.
À
[22] For palladium-catalyzed nucleophilic aromatic C H functional-
ization processes involving dearomatization mechanism, see:
4
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a) allylation: M. Bao, H. Nakamura, Y. Yamamoto, J. Am.
Chem. Soc. 2001, 123, 759. Related computational studies: A.
Ariafard, A. Lin, J. Am. Chem. Soc. 2006, 128, 13010;
b) amination: S. Zhang, Y. Wang, X. Feng, M. Bao, J. Am.
Chem. Soc. 2012, 134, 5492; Related computational studies: H.
Xie, H. Zhang, Z. Lin, Organometallics 2013, 32, 2336.
[23] For a copper-catalyzed 1,3-hologen migration by an oxidative
addition mechanism, see: R. D. Grigg, R. Van Hoveln, J. M.
Schomaker, J. Am. Chem. Soc. 2012, 134, 16131.
[24] An alternative mechanism involving oxidative addition to
a copper(III) intermediate is also possible, see Ref. [7].
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Communications
À
C H Activation
Y. Yang, S. L. Buchwald*
&&&& — &&&&
À
Copper-Catalyzed Regioselective ortho C
H Cyanation of Vinylarenes
À
Reaction combo: A combined copper-
ortho-selective C H functionalization of
À
catalyzed hydroborylation/ortho C H
arenes and anti-Markovnikov hydrofunc-
tionalization of the pendant olefin (see
scheme; Pin=pinacolato, Ts=4-tolue-
nesulfonyl).
cyanation of vinylarenes is described,
thus allowing the selective functionaliza-
tion of vinylarenes and featuring unique
site selectivity. The reaction leads to
6
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